Non-binding site modulation of G protein-coupled receptor signalling

G protein-coupled receptors (GPCRs) are by far the most successful drug tar gets yet known, due to their key role in cellular communication. Historical ly, these drugs bind to the same site at which the endogenous agonist inter acts. However, as the details of cell signalling are clarified, it is becom ing apparent that there are many other sites at which GPCR signalling can b e modulated. Furthermore, the emerging ability to block protein-protein int eractions with small molecules means that these sites are now also viable t herapeutic targets. Potential points of therapeutic intervention of GPCR si gnalling are at the level of the G protein, where the activities of both a and py subunits could be controlled; at multiple effecters such as the aden ylyl cyclases, phospholipases and phosphodiesterases; at regulatory protein s such as the regulators of G protein signalling (RGS) proteins or receptor kinases; or at the mitogenic pathways, which offer many sites for interven tion. By targeting these sites, perhaps just one arm of the multiple pathwa ys through which a receptor works can be modified, thus providing a greater degree of therapeutic selectivity and specificity than can be attained usi ng receptor agonists or antagonists.